E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type II diabetes mellitus. |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate the efficacy of SYR-322 administered in combination with metformin as compared with metformin alone on glycosylated hemoglobin (HbA1c) change from baseline |
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E.2.2 | Secondary objectives of the trial |
• To evaluate other measures of glycemic control after treatment with SYR-322 in combination with metformin as compared with metformin alone • To evaluate changes in pancreatic function after treatment with SYR-322 in combination with metformin as compared with metformin alone • To evaluate changes in body weight following treatment with SYR-322 in combination with metformin as compared with metformin alone • To evaluate the safety of SYR-322 in combination with metformin as compared with metformin alone • To evaluate plasma concentrations of SYR-322 using a sparse sampling approach • To evaluate clinically meaningful levels of response in HbA1c after treatment with SYR-322 in combination with metformin as compared with metformin alone |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible for this study, each of the following criteria must be satisfied with a “YES” answer (unless not applicable): • Males or females, 18 to 80 years of age, inclusive, with a historical diagnosis of type 2 diabetes mellitus who are currently treated with metformin alone but who are experiencing inadequate glycemic control. The subject should have received the metformin monotherapy for at least the 3 months prior to Screening; and the subject must have a stable dose ≥1500 mg metformin for at least 8 weeks prior to randomization. Subjects with a maximum tolerated dose that is documented to be less than 1500 mg of metformin may also be enrolled if this dose has been stable for 8 weeks prior to randomization. • No treatment with antidiabetic agents other than metformin within the 3 months prior to Screening. (Exception: if a subject has received other antidiabetic therapy for less than 7 days within the 3 months prior to Screening.) • Body mass index ≥23 kg/m2 and ≤45 kg/m2 • Fasting C-peptide concentration ≥0.8 ng/mL (≥0.26 nmol/L). (If this screening criterion is not met, the subject still qualifies if C-peptide ≥1.5 ng/mL (≥0.50 nmol/L) after a challenge test. See Appendix E.) • HbA1c concentration between 7.0% and 10.0%, inclusive • If regular use of other, nonexcluded medications, must be on a stable dose for at least the 4 weeks prior to Screening. However, PRN (as needed) use of prescription or over-the-counter medications is allowed at the discretion of the investigator. • Systolic blood pressure ≤180 mm Hg and diastolic pressure ≤110 mm Hg • Hemoglobin ≥12 g/dL (≥120 gm/L) for males and ≥10 g/dL (≥100 gm/L) for females • Alanine aminotransferase ≤3 x upper limit of normal • Serum creatinine <1.5 mg/dL (<133 micromol/L) for males and <1.4 mg/dL (<124 micromol/L) for females. • Thyroid-stimulating hormone level ≤ the upper limit of the normal range and the subject is clinically euthyroid • Neither pregnant (confirmed by laboratory testing in females of childbearing potential) nor lactating • Female subjects of childbearing potential (ie, not surgically sterile and/or not postmenopausal) must be practicing adequate contraception. Methods of adequate contraception include the following: intrauterine device; doublebarrier device such as a diaphragm or condom plus spermicide; or a hormonal contraceptive (including injectable, implantable, or oral). Adequate contraception must be practiced for the duration of participation in the study. • Able and willing to monitor their own blood glucose concentrations with a home glucose monitor • No major illness or debility that in the investigator’s opinion prohibits the subject from completing the study • Able and willing to provide written informed consent
Additional Inclusion Criteria for Randomization: In order to be eligible for randomization, each of the following additional criteria must be satisfied with a “YES” answer: • HbA1c concentration between 7.0% and 10.0%, inclusive at the Week -1 visit. (Of note, if the subject does not qualify for randomization based on this criterion, the assessment may be repeated on a weekly basis, for a maximum of 4 additional weeks.) • Fasting plasma glucose <275 mg/dL (<15.27 mmol/L) at week - 1 visit. (Of note, if the subject does not qualify for randomization based on this criterion, the assessment may be repeated on a weekly basis, for a maximum of 4 additional weeks). • Have been at least 75% compliant with the single-blind placebo regimen during the run-in/stabilization period, as assessed by tablet count • No use of oral or systemically injected glucocorticoids or use of weight-loss drugs is allowed within the 3 months prior to randomization. (Inhaled corticosteroids are allowed.) |
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E.4 | Principal exclusion criteria |
In order to be eligible for this study, each of the following criteria must be satisfied with a “NO” answer: • Urine albumin/creatinine ratio of >1000 μg/mg (> 113 mg/mol) at Screening. If elevated, the subject may be rescreened within 1 week. • History of cancer, other than squamous cell or basal cell carcinoma of the skin, that has not been in full remission for at least 5 years prior to Screening. (A history of treated CIN I or CIN II [cervical intraepithelial neoplasia] is allowed.) • History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening • History of treated diabetic gastric paresis • New York Heart Association Class III or IV heart failure regardless of therapy. Currently treated subjects who are stable at Class I or II are candidates for the study (see Appendix F). • History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 6 months prior to Screening • History of any hemoglobinopathy that may affect determination of HbA1c • History of infection with hepatitis B, hepatitis C, or human immunodeficiency virus • History of a psychiatric disorder that will affect the subject’s ability to participate in the study • History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors • History of alcohol or substance abuse within the 2 years prior to Screening • Receipt of any investigational drug within the 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within the 3 months prior to Screening • Prior treatment in an investigational study of SYR-322 |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be change from baseline in HbA1c at Week 26. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of the last subject. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |